Composition containing iminoethanophenanthrene derivatives and method of use

ABSTRACT

The internal administration of d-1, 3, 4, 9, 10, 10a-hexahydro6-methoxy-11-methyl-2H-10, 4a-iminoethanophenanthrene acid addition salts to the human male in doses from about 0.025 g. to about 0.725 g. substantially diminishes the ability to ejaculate and the quantity of living sperm ejaculated. This material, when administered in the proper quantities, is useful for reducing the possibility of pregnancy in human females.

United States Patent [191 Spain 51 Sept. 2, 1975 COMPOSITION CONTAINING IMINOETHANOPHENANTHRENE DERIVATIVES AND METHOD OF USE [75] Inventor:

[73] Assignees: Fred L. Denson; Myron B.

Kurtzman; Chauncey F. Levy, all of Rochester, NY.

[22] Filed: Apr. 9, 1974 [21] Appl. No.: 459,314

Related U.S. Application Data [63] Continuation-in-part of Ser. No. 187,144, Oct. 6, 1971, abandoned, which is a continuation of Ser. No. 22,695, March 25, 1970, abandoned.

Levern Spain, Rochester, NY.

[52] U.S. Cl. 424/260 [51] Int. Cl. A61K 27/00 [58] Field of Search 424/260 [56] References Cited UNITED STATES PATENTS 3,427,379 2/1969 Barry et al. 424/260 Primary ExaminerStanley J. Friedman Attorney, Agent, or F irmDenson and Kurtzman [57] ABSTRACT 27 Claims, N0 Drawings COMPOSITION CONTAINING IMINOETHANOPHENANTHRENE DERIVATIVES AND METHOD OF USE This application is a continuation-in-part of Ser. No. 187,144, filed Oct. 6, 1971, of Levern Spain and now abandoned, which in turn is a continuation of Ser. No. 22,695, filed Mar. 25, 1970, by Levern Spain and now abandoned, and entitled, NOVEL PROCESS.

This invention relates to a novel process for controlling the ability of the male to ejaculate and the quantity of living sperm ejaculated.

Many types of birth control devices are available. Mechanical devices are generally considered to be safer from a health standpoint than internally administered drugs (e.g., oral contraceptives). Techniques designed for internal administration of a drug are obviously more satisfactory and frequently more efficient for reducing the possiblity of pregnancy than mechanical methods. However, internally administered drugs can be potentially hazardous from a health standpoint since they are generally taken over a long period of time and during such protracted period, can produce OCH undesirable side effects. Moreover, it is unfortunate that most devices, mechanical as well as drugs, are designed to be utilized only by the female.

The variety of mechanical birth control devices available for use by males are far less numerous than those available to females. Internally administered birth control drugs for males are presently not commercially available. Theoretically, such drugs can function in any of several modes. Ideally, such durgs can prevent ejaculation completely or can permit ejaculation of less than the threshold number of living sperm required for fertilization purposes. Richard D. Amelar, M.D., F.A.C.S. in lnfertility In Men, F. A. Davis Company, 1966, p. 36, make reference to V. MacLeod who considers that true oligospermia is represented by sperm counts under 20 million per ml of ejaculate, and that with sperm counts below million per ml, it is unlikely that fertilization of the ovum will occur. Alternatively, they can permit complete ejaculation of a sterile semenal fluid. Thus far, relatively little research has been directed toward finding drugs which are designed for administration to males for the purpose of suppressing or preventing ejaculation, but which cause little or no undesirable side effects when used over long periods.

It is an object of this invention to provide a novel pro cess for substantially reducing the ability of the male to ejaculate.

It is another object of this invention to provide a composition for substantiallyreducing the ability of the male to ejaculate.

It is still another object to provide a process and composition which can delay the male ejaculation.

It is another object of this invention to provide a novel process and composition for preventing the male from ejaculating.

A further object of this invention is to provide a novel process and composition for reducing the quantity of living sperm ejaculated by the male.

Still a further object is to provide a process and product for reducing the quantity of living sperm ejaculated by a male below the threshold amount required to impregnate a female.

It is yet another object of this invention to provide an internally administered male birth control composition.

These and other objects are accomplished by internally administering to the human male a dose of a composition containing a medicinally acceptable acid addition salt of d-l 3, 4, 9, 10, l0a-hexahydro-6-methoxyl 1-methyl-2H-10, 4a-iminoethanophenanthrene (HMMIEP) which has the following structure:

It has surprisingly been found that the internal administration of a pharmaceutical composition containing a prescribed quantity of a HMMIEP acid salt substantially can delay the occurrence of the male ejaculation or substantially abate the ability to ejaculate. By increasing the quantity of HMMIEP acid salt in the composition, the ability to ejaculate is even further diminished to the point where it is actually prevented for periods of up to about 15 hours. In preferred dosage quantities, ejaculation can be delayed from 5 minutes to about 4 hours, and preferably 5 minutes to about 15 minutes. It has also been expectedly discovered that an internally administered quantity of HMMIEP acid salt reduces the amount of semen and living sperm ejaculated. This reduction in the amount of semen and sperm ejaculated concomitantly greatly reduces the possibility of fertilization of the female ovum.

fully employed in accordance with the invention ranges in the amount of about 0.06 g. to about 0.725 g. Preferably, the quantity of each HMMIEP acid salt which can be employed in accordance with the invention is in the range of about 0.080 g. to about 0.325 g. In an especially preferred aspect of the invention, the quantity of I-IMMIEP acid salt which can be advantageously employed is in the range of about 0.080 g. to about 0.200

The effect of the HMMIEP acid salt begins from about 25 minutes to about one hour after administration and lasts from about 12 to about 15 hours. The HMMIEP acid salt will decrease the live sperm count of a normal male to an amount which is considered to cause a healthy, normal male to be unfertile. The live sperm count decreases with an increase in the dosage of the HMMIEP which is internally administered to a male. In the range from around 0.250 g. and upward, the live sperm count is substantially reduced to zero. In the lower ranges, the sperm count is reduced to about below ten million per ml ejaculation. It has also been unexpectedly discovered that with increasing dosage, there is an accompanying increasing delay toward the point of ejaculation during the physical stimulation of the male sex organ. For the preferred dosage range of from about 0.080 g. to about 0.200 g. of HMMIEP acid salt, this delay period ranges from about 15 minutes to about one-half hour after initiation of stimulation. The effect of HMMIEP on decreasing the sperm count generally will begin to decrease after several hours, nevertheless, true oligospermia is maintained for about 15 hours. In order to maintain the effect over the 15-hour period relatively constant or to extend the period of oligospermia, the HMMIEP can be contained in time release systems so as to obtain timed release of l-IMMIEP. The time release system employed can be any of the several methods which are presently known or yet to be discovered. For example, the HMMIEP can be encapsulated in materials which will dissolve in the body at different rates.

The pharmaceutical composition administered in the prescribed dosage amounts according to this invention can contain the HMMIEP acid salt as a sole pharmaceutically active ingredient. The composition can be administered as a sole ingredient or it can be contained in a pharmaceutical composition.

The manner in which the presently disclosed products are formulated into suitable pharmaceutical compositions will be readily apparent to those skilled in the art. In general, any of the procedures or techniques known in the art can be employed in the preparation of oral dosage forms containing the present products. The various optional ingredients which are used normally in the preparation of tablets, lozenges, suspensions, solutions, etc., can be used in preparing the present products into marketable, pharmaceutical compositions. For example, any of the well-known coloring agents, sweetening agents, flavoring agents, perfuming agents, etc., can be used in the preparation of such compositions. Moreover, these compositions can contain adjuvants, either organic or inorganic in nature, such as gelatin, starch, magnesium stcarate, talc, vegetable oils, gums, polyalkylerie glycols, preservatives, stabilizers, wetting or emulsifying agents, salts for altering osmotic pressure, buffers, etc.

A dose of the pharmaceutical composition described herein can be administered internally by any of several well-known techniques, e.g., orally, subcutaneously or intravenously. Oral administration of HMMIEP acid salt represents the preferred mode. Oral administration of HMMIEP acid salt has been used previously; i.e., when HMMIEP acid salt has been employed as a cough suppressant to arrest respiratory ailments. However. the invention as described herein is differentiated from the aforementioned use in that the dosage requirements are substantially different, the quantity of HMMlEP acid salt administered for cough suppressant purposes having virtually no effect on the ability of the male to ejaculate or on the quantity of living sperm or semen produced by ejaculation.

The HMMIEP acid addition salts described herein are suitable for use in the production of the various liquid or solid dosage forms in which pharmaceutical preparations are normally provided. For example, since these materials are water soluble, they are readily dissolved in aqueous vehicles. Also, they can be dispersed, suspended or dissolved in pharmaceutically acceptable liquids or syrups. Moreover, these materials are completely suitable for use in the preparation of dry products such as tablets, lozenges, candies, powders, capsules, etc. It is further understood that by dosage amounts or dosage units, it is the total quantity of HMMIEP internally administered whether in the form of for example one or more capsules.

In one embodiment of this invention, therefore, there is provided a process for substantially diminishing the human males ability to ejaculate comprising internally administrating to a male a dose of a pharmaceutical composition comprising from about 0.06 g. to about 0.725 g. of a d-l, 3, 4, 9, 10, 10a-hexahydro-6- methoxy- 1 1 -methyl-2H- 10, 4a-iminoethanophenanthrene acid addition salt. In another embodiment of this invention, there is provided a pharmaceutical composition for reducing the human male sperm count so as to substantially cause oligospermia and substantially prevent fertilization of the human ovum said composition comprising from about 0.06 g. to about 0.725 g. d-l, 3, 4, 9, l0, 10a-hexahydro-6-methoxy-11-methy1-2H-10, 4a-iminoethanophenanthrene acid addition salt. In still another embodiment of this invention, there is pro vided a process of substantially reducing the human male live sperm count to below the threshold amount generally recognized as required for male fertility, said process comprising the internal administration of a pharmaceutical composition comprising d-l, 3, 4, 9, l0, l0a-hexahydro-6-methoxy-l 1-methyl-2H- l 0, 4a-iminoethanophenanthrene acid addition salt. More particularly, the sperm count can be reduced so as to cause oligospermia and perferrably reduced to below about 10 million living sperm per ml of ejaculation.

HMMIEP acid addition salts can be prepared by any of the several known techniques. Typical syntheses are described in Schnider et al: Helv. Chem. Acta, 34:2211,1951; Bien et al: J. Chem. Soc. 1963: 2065-2068; Swiss Patent 301 ,670; British Patent 624,391; Schnider et al: Helv. Chem. Acta, 32:82], 1949.

The safety of HMMIEP acid addition salts has been thoroughly investigated with respect to toxicity, addiction liability, harmful side effects, etc. at the dosage levels of this invention. They have been found to be non-toxic and to have no addiction liabilities; these finding being synonymous with those described in Benson et al., J. Pharm and Exp. Ther. 109: l 89, 1953; and

Example I Preparation of HMMIEP-HBr HMMIEP hydrobromide is prepared according to the method of Bien et al: J. Chem. Soc. 1963: 2065-2068. The synthesis uses 2-m-methoxyphenyl-3-oxoeyclohexylacetic acid (I) as the starting material and involves the following reactions:

lizations, pure 4-(ethylene ketal) of 1,2,3,4,4a,9,l0, la-octahydrol 0-hydroxyimino-6-methoxy-4,9- dioxophenanthrene (IV) is obtained.

V. Crude IV is reduced catalytically in batches of 0.6 g. Ethanol (25 ml) concentrated hydrochloric acid (0.8 ml) and 10% palladized carbon (0.15 g) are shaken under hydrogen, and the crude oxime (0.6 g) added in small portions; each new portion is added after hydrogen uptake ceases. Catalyst and solvent are removed. Trituration of the residue with acetone gives the 4- (ethylene ketal) of lO-amino-l,2,3,4,4a,9,l0,l()aoctahydro-6-methoxy4,9-dioxophenanthrene (V).

VI. Crude V (2.75 g) is dissolved with stirring in an ice-cold mixture of dry chloroform (145 ml) and dry triethylamine (2.5 ml). Acetylglycollyl chloride (1.31

Reagents: 1, HF. 2, (CH 'OH) -p-C H Me'SO H. 3, n-C I-I 'ONO-NaOEt. 4, H -Pd-C-I-ICI. 5, AcOCH COCI'NEt 6, Aq. AcOI-I. 7, I-IuangMinlon, LiAII-I H'CO H-CH Q.

II. 2-m-methoxyphenyl-3-oxocyclohexylacetic acid (I) (55g) is treated with anhydrous hydrogen fluoride (900 ml). After 4 hours the hydrogen fluoride is removed by a stream of dry air and the residual oil is crystallized. The mixture is made alkaline with dilute sodium hydrogen carbonate solution and the crude product removed and washed with water. Upon recrystallization, l ,2,3,4,4a,9,10, lOa-octahydro-6-methoxy-4,9- dioxophenanthrene (II) is obtained.

III. A mixture of the diketone (Il)( 10g), ethylene glycol (2] ml), benzene (43 ml), and toluene-p-sulphonic acid (0.5 g) is refluxed for 3 hours, the water formed being removed azeotropically. The mixture is cooled and neutralized with sodium methoxide. The benzene layer is separated and the glycol layer diluted with water and extracted with benzene. The combined benzene solutions are washed with water, dried and evaporated. Trituration of the residue with methanol gives 11g crude product. After three recrystallizations the 4-(ethylene ketal) of l,2,3,4,4a,9,l0,IOa-octahydro-6- methoxy-4,9-dioxophenanthrene (III) is obtained.

IV. A solution of III (4.2 g) in 18 ml of dry tetrahydrofuran is added to an ice-cold solution of sodium ethoxide (0.37 g of sodium in 7.5 ml of dry ethanol). The mixture is stirred and n-pentyl nitrite is added. After 48 hours, the brown solution is diluted with water, 10% sodium hydroxide solution (20 ml) is added, and the entire mixture extracted with ether. The crude product is precipitated from the alkaline solution by saturation with carbon dioxide. After several recrystalg) in chloroform (82 ml) is added dropwise with stirring and cooling for 1 hour, and then the mixture is refluxed for minutes. The solution is cooled, washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate, and water and dried. An oil is obtained which produces crystals upon trituration. Recrystallization from methanol gives 4-(ethylene ketal) of 10- acetoxyacetamidol ,2,3,4,4a,9,10,lOa-octahydro-6' methoxy-4,9-dioxophenanthrene (VI).

VII. Crude VI (2.4 g) is heated in 50% aqueous acetic acid (30 ml) at 100 for 30 minutes. The solution is cooled and poured into an excess of dilute sodium hydrogen carbonate solution and the whole is extracted with chloroform. The oil obtained on evaporation is crystallized on trituration with etherchloroform. The solid is filtered to give lO-acetoxyamidol,2,3,4,4a,9, l 0, l Oa-octahydro-6-methoxy-4,9- dioxophenanthrene (VII).

VIII. A mixture of crude VII 1.75 g), ethylene glycol (10 ml), toluene (16 ml), benzene (10 ml), and

'toluene-p-sulphonic acid mg) is refluxed for 6 hours under an azeotropic separator to collect volatile products. After cooling, sodium methoxide is added until a slightly alkaline reaction is obtained and the two layers are separated. The ethylene glycol layer is diluted with water and extracted with chloroform, and the combined organic layers are dried and evaporated. Trituration of the residue with benzene gives crystals which upon recrystallization from isopropanol gives 4' (ethylene ketal) of the dioxo-lactam (VIII).

IX. The ketal (VIII)(0.35 g) is heated in aqueous acetic acid (30 ml) at for 1 hour. The solution is cooled, neutralized with dilute sodium hydrogen carbonate solution, and extracted with chloroform. After evaporation of the solvent the residue is triturated with ethyl acetate, giving 3-methoxy-5,10,16-trioxomorphenan (IX).

X. A solution of IX l 15 mg) is submitted to the conditions of the Huang-Minlon procedure with hydrazine hydrate (0.5 ml), potassium hydroxide (0.2 g) and diethylene glycol (3 ml). After 4 hours heating at 180 the mixture is worked up to obtain a light brown lactum oil. This material is dissolved in tetrahydrofuran and treated with an excess of lithium aluminum hydride (0.5 g). After refluxing for 8 hours, an oily crude amine is isolated and redissolved in formic acid (0.5 ml). Thirty percent (30%) aqueous formaldehyde (0.2 ml) is added, and the mixture is refluxed for 8 hours. The product obtained is removed from the reaction medium and extracted with chloroform. Solvent is removed and the residue is recrystallized three times from ethermethanol to give 1,3,4,9,10,10a-hexahydro-6- methoxy-1 l-methyl-2l-I- l O, 4a-iminoethanophenanthrene (X). The product is treated with aqueous hydrobromic acid to give the hydrobromide addition salt.

Example 11 Table I a) Dosage 355 (amount of HMMlEP-HBr administered in mg.)

b) No. of experiments 9 c) No. of (b) unable to 9 ejaculate d) No. of (b) able to ejaculate This Example demonstrates that a male human is prevented from ejaculating from 1.5 hours to at least 5.5 hours after oral administration of 355 mg. of the hydrobromide salt of HMMIEP. During this period of time, a normal erectile state of the penis was maintained.

Example 111 Example I] is repeated except that the dose of HMMIEP-I-IBr is prepared in capsular form. In this case, a capsule containing 325 mg. of HMMIEP-HBr is orally administered to a human male. Observations similar to those described in Example 11 are made. The results are set forth in the following Table II:

Table II a) Dosage 325 (amount of HMMlEP-HBr) administered in mg.) b) No. of experiments 15 c) No. of (b) unable to ejaculate l5 d) No. of (b) able to ejaculate 0 This Example demonstrates that a male human is prevented from ejaculating from 1.5 hours to at least 5.5 hours after oral administration of 325 mg. of HMMIEP- HBr. During this period of time, a normal erectile state of the penis was maintained.

Example lV Example 11 is repeated except the solution contains 177 mg. of HMMlEP-HBr in 60 g. distilled water. Ob-

The sperm count in all instances was greatly below that amount considered necessary to fertilize a female ovum under normal conditions.

Example V Example IV is repeated except the dose of HMMIEP- HBr is prepared in capsular form. In this case, a capsule containing mg. of HMMlEP-HBr is orally administered to a human male. Observations similar to those described in Example IV are made. All specimens ejac ulated within 1 hour after administration. The sperm count in all instances was about 3.0 X 10 per ml.

Example VI The purpose of this Example is to demonstrate the correlation between dosage amount and the corresponding time period of inability to ejaculate. In each case, HMMlEP-HBr is orally administered as a solution. The results are set forth in the following Table IV:

Table IV Average Time Dosage Experiments for Ejaculation 355 6 4 hours 6 1 hour This Example demonstrates that the inability to ejaculate increases with increasing dosages of HMMIEP- HBr. The sperm count in all instances was lower than 10 X 10 sperm/ml of semen.

Example VIII The purpose of this Example is to demonstrate that the amount of semenal fluid ejaculated decreases with increasing dosages of HMMlEP-HBr. The quantity of semenal fluid ejaculate after oral administration of 177 mg. of HMMIEP-HBr is found to be about onetenth of the amount of semen ejaculated by control specimens i.e., specimens to whom no administration is made. Such a small amount of ejaculated semen is generally considered insufficient, according to statistical probability, to cause fertilization of the female ovum by the sperm carried therein.

No semen is ejaculated within four hours of the oral administration of 325 mg. of HMMlEPJ-IBr.

Example lX Several male rats are given various dosages of HMMIEP-HBr orally in a manner similar to that described in Example ll. After the administrations are completed, each male rat is mated with a female rat. The vagina of each of the female rats is then examined for the presence of semen. Concurrent with the mating of the administered rats, control rats which have not been given HMMIEP-HBr are also mated under the same conditions. The results of these experiments are set forth in the following Table V:

Table V 7. The process of claim 1 wherein said pharmaceutica] composition comprises the hydrobromide salt of d-l, 3, 4, 9, l0, lOa-hexahydro-6-methoxy-l l-methyl- 2H- 1 0, 4aiminoethanophenanthrene.

8. The process of claim 1 wherein said pharmaceuti' cal composition is a solid.

9. The process of claim 1 wherein said pharmaceutical composition is a liquid.

10. The process of claim 2 wherein said pharmaceutical composition is contained in time release capsules so as to obtain time release action.

TEST NUMBER A. B. C. F.

0 (control) "'Rnts did not mate in 3 ex eriments. "Rms did not mate in 3 experiments. ""Each control female rat became pregnant.

The results of this Example demonstrate that male rats receiving an administration of 2 or more mg/kg of HMMlEP-l-lBr did not eject any semenal fluid during mating. One mg/kg of HMMlEPJ-lBr permitted ejection of a small amount of semenal fluid but not enough to cause the female counterpart to become pregnant. All male rats receiving no HMMIEP-HBr ejected semenal fluid and pregnancies resulted.

The invention has been described in detail with particular reference to preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.

I claim:

1. A process for substantially diminishing the human males ability to ejaculate comprising internally administering to said male a dose of a pharmaceutical composition comprising from about 0.06 g. to about 0.725 g. of a d-l, 3, 4, 9, l0, l0a-hexahydro-6-methoxy-l lmethyl-ZH-IO, 4a-iminoethanophenanthrene acid addition salt.

2. The process of claim 1 wherein the organic acid addition salt is administered orally.

3. The process of claim l'wherein the organic acid addition salt is administered subcutaneously.

4. The process of claim 1 wherein the organic acid addition salt is administered intravenously.

5. The process of claim 1 wherein the amount of the organic acid addition salt administered in said dose ranges from about 0.08 g. to about 0.325 g.

6. The process of claim 1 wherein the amount of the organic acid addition salt is administered in said dose ranges from about 0.08 g. to about 0.200 g.

l l. The process of claim 1 wherein the ability to ejaculate is substantially diminished for a period from about 1.5 hours to about 12.0 hours after said pharmaceutical composition is administered.

12. A process for preventing the human male s ability to ejaculate comprising orally administering to said male a dose of a pharmaceutical composition comprising from about 0.080 g. to about 0.200 g. of d-l, 3, 4, 9, 10, 10a-hexahydro-6-methoxy1 l-methy1-2H-l 0, 4a-iminoethanophenanthrene hydrobromide thereby preventing said male from ejaculating for a period from about 5 minutes to about 15 minutes after the effect of said administration has begun.

13. A pharmaceutical composition in dosage unit form comprising from about 0.06 g. to about 0.725 g. of a d-l, 3, 4, 9, l0, l0a-hexahydro-6-methoxy-l lmethyl-2H10, 4a-iminoethanophenanthrene acid addition salt per dosage quantity and a pharmaceutical 20. The pharmaceutical composition of claim 16 in capsular form.

21. A pharmaceutical composition in dosage unit form comprising from about 0.080 g. to about 0.325 g. of d-l, 3, 4, 9, l0, la-hexahydro-6-methoxy-1lmethyl-2H-l0, 4a-iminoethanophenanthrene hydrobromide.

22. A pharmaceutical composition of claim 21 in dosage unit form comprising from about 0.080 g. to about 0.200 g. of d-l, 3, 4, 9, l0, l0a-hexahydro-6- methoxy-l l-methyl-2H- l O, 4a-iminoethanophenanthrene hydrobromide.

23. A process for substantially reducing the amount of living sperm present in a human males ejaculation comprising internally administrating to said male a pharmaceutical composition comprising from about 12 0.06 g. to about 0.725 g. of a d-l, 3, 4, 9, 10, 10aheXahydro-6-methoxy-l l-methyl-2H-10, 4a-iminoethanophenanthrene acid addition salt.

24. The process of claim 23 wherein the sperm count is reduced below the threshhold amount for fertility.

25. The process of claim 23 wherein said acid addition salt is d-l, 3, 4, 9, l0, l0a-hexahydro-6-methoxyl l-methyl-2H-l0, 4a-iminoethanophenanthrene hydrobromide.

26. The process of claim 25 wherein said dosage amount is in the range of from about 0.08 g. to about 0.325 g.

27. The process of claim 23 wherein the living sperm count is reduced to below about 10 million per ml of ejaculation. 

1. A PROCESS FOR SUBSTANTIALLY DIMINISHING THE HUMAN MALE''S ABILITY TO EJACULATE COMPRISNG INTERNALLY ADMINISTERING TO SAID MALE A DOSE OF A PHARMACEUTICAL COMPOSITION COMPRISING FROM ABOUT 0.006G. TO ABOUT 0.725G. OF A D-1, 3,J,9,10, 10A-HEXAHYDRO-6-METHOXY-11-METHYL-2H-10. 4A-IMINOETHANOPHENANTHRENE ACID ADDITION SALT.
 2. The process of claim 1 wherein the organic acid addition salt is administered orally.
 3. The process of claim 1 wherein the organic acid addition salt is administered subcutaneously.
 4. The process of claim 1 wherein the organic acid addition salt is administered intravenously.
 5. The process of claim 1 wherein the amount of the organic acid addition salt administered in said dose ranges from about 0.08 g. to about 0.325 g.
 6. The process of claim 1 wherein the amount of the organic acid addition salt is administered in said dose ranges from about 0.08 g. to about 0.200 g.
 7. The process of claim 1 wherein said pharmaceutical composition comprises the hydrobromide salt of d-1, 3, 4, 9, 10, 10a-hexahydro-6-methoxy-11-methyl-2H-10, 4a-iminoethaNophenanthrene.
 8. The process of claim 1 wherein said pharmaceutical composition is a solid.
 9. The process of claim 1 wherein said pharmaceutical composition is a liquid.
 10. The process of claim 2 wherein said pharmaceutical composition is contained in time release capsules so as to obtain time release action.
 11. The process of claim 1 wherein the ability to ejaculate is substantially diminished for a period from about 1.5 hours to about 12.0 hours after said pharmaceutical composition is administered.
 12. A process for preventing the human male''s ability to ejaculate comprising orally administering to said male a dose of a pharmaceutical composition comprising from about 0.080 g. to about 0.200 g. of d-1, 3, 4, 9, 10, 10a-hexahydro-6-methoxy-11-methyl-2H-10, 4a-iminoethanophenanthrene hydrobromide thereby preventing said male from ejaculating for a period from about 5 minutes to about 15 minutes after the effect of said administration has begun.
 13. A pharmaceutical composition in dosage unit form comprising from about 0.06 g. to about 0.725 g. of a d-1, 3, 4, 9, 10, 10a-hexahydro-6-methoxy-11-methyl-2H-10, 4a-iminoethanophenanthrene acid addition salt per dosage quantity and a pharmaceutical carrier therefore.
 14. The pharmaceutical composition of claim 13 in oral dosage form.
 15. The pharmaceutical composition of claim 13 in liquid dosage form.
 16. The pharmaceutical composition of claim 13 in solid dosage form.
 17. The pharmaceutical composition of claim 13 in variable time release capsules.
 18. The pharmaceutical composition of claim 13 wherein the acid addition salt is d-1, 3, 4, 9, 10, 10a-hexahydro-6-methoxy-11-methyl-2H-10, 4a-iminoethanophenanthrene hydrobromide.
 19. The pharmaceutical composition of claim 13 in the form of a powder.
 20. The pharmaceutical composition of claim 16 in capsular form.
 21. A pharmaceutical composition in dosage unit form comprising from about 0.080 g. to about 0.325 g. of d-1, 3, 4, 9, 10, 10a-hexahydro-6-methoxy-11-methyl-2H-10, 4a-iminoethanophenanthrene hydrobromide.
 22. A pharmaceutical composition of claim 21 in dosage unit form comprising from about 0.080 g. to about 0.200 g. of d-1, 3, 4, 9, 10, 10a-hexahydro-6-methoxy-11-methyl-2H-10, 4a-iminoethanophenanthrene hydrobromide.
 23. A process for substantially reducing the amount of living sperm present in a human male''s ejaculation comprising internally administrating to said male a pharmaceutical composition comprising from about 0.06 g. to about 0.725 g. of a d-1, 3, 4, 9, 10, 10a-hexahydro-6-methoxy-11-methyl-2H-10, 4a-iminoethanophenanthrene acid addition salt.
 24. The process of claim 23 wherein the sperm count is reduced below the threshhold amount for fertility.
 25. The process of claim 23 wherein said acid addition salt is d-1, 3, 4, 9, 10, 10a-hexahydro-6-methoxy-11-methyl-2H-10, 4a-iminoethanophenanthrene hydrobromide.
 26. The process of claim 25 wherein said dosage amount is in the range of from about 0.08 g. to about 0.325 g.
 27. The process of claim 23 wherein the living sperm count is reduced to below about 10 million per ml of ejaculation. 